The metabolic syndrome including type 2 diabetes mellitus, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinaemia, possibly type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins), small dense LDL particles and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In type 2 diabetes mellitus atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is awareness of the need to increase the insulin sensitivity in patients with the metabolic syndrome and thus to correct the dyslipidaemia which is considered to cause the accelerated progress of atherosclerosis. However, currently this is not a universally accepted diagnosis with well-defined pharmacotherapeutic indications.
The S-enantiomer of the compound of formula A below
2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, is disclosed in PCT Publication Number WO99/62872. This compound is reported to be a modulator of peroxisome proliferator-activated receptors (PPAR, for a review of the PPARs see T. M. Willson et al, J Med Chem 2000, Vol 43, 527) and has combined PPARα/PPARγ agonist activity (Structure, 2001, Vol 9, 699, P. Cronet et al). This compound is effective in treating conditions associated with insulin resistance.
Co-pending PCT application No. PCT/GB02/05743 discloses a compound of formula A
wherein R1 represents chloro, fluoro or hydroxy as well as optical isomers and racemates thereof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, processes for preparing such compounds, to their the utility in treating clinical conditions including lipid disorders (dyslipidemias) whether or not associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.
WO 02/100813 discloses that compounds of formula C
in which Ar is a substituted or unsubstituted aromatic group; Q is a covalent bond, —CH2— or CH2—CH2—; W is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene linking group from 2 to 10 atoms in length; the phenyl ring is optionally substituted with up to four substituents in addition to R1 and W; and R1 is inter alia —(CH2)n—CH(OR2)—(CH2)mE or —(CH)═C(OR2)—(CH2)mE wherein E is inter alia COOR3; R2 is H, an aliphatic group etc.; R3 is H, an aliphatic group etc.; and n and m are independently 0, 1 or 2; are modulators of PPAR receptors.
Surprisingly a select series of compounds has now been found which are dual PPARα/PPARγ modulators.